Researchers discover DNA copy number alterations lead to changes in RNA circuits that impact melanoma metastasis

MicroRNA (miRNA) molecules are small segments of nonprotein coding RNA that can silence other protein-coding RNA molecules and regulate the production of proteins. When the activity of miRNA molecules is perturbed, diseases such as cancer can develop. Recently, it has been shown that this regulation also works in the opposite direction, where protein coding RNAs act as "sponges" to bind to miRNA molecules and block their function. RNAs affecting the function of miRNAs are called competitive endogenous RNA (ceRNA) and are thought to play an important role in cancer development independent of their protein-coding activity.

The existence of ceRNA has been known since approximately 2010, but its impact on cancer development is not well understood. Since DNA copy number alterations impact cancer, Moffitt researchers wanted to determine whether these DNA alterations can drive cancer development through ceRNAs.

The team analyzed chromosome alterations and discovered that gains in chromosome segment 1q were very common among a panel of metastatic melanoma cases. A more in-depth analysis revealed that three key genes called CEP170, NUCKS1andZC3H11A present on chromosome 1q are amplified in metastatic melanoma cases and associated with disease progression.

Given the potential clinical implications of these alterations, the researchers wanted to understand the molecular contributions of CEP170, NUCKS1andZC3H11Ato melanoma development. They performed a series of laboratory experiments and discovered that the RNA sequences of CEP170, NUCKS1andZC3H11A promote cell growth, migration and invasion in melanoma cell lines, and stimulated metastasis growth in mouse models of melanoma, independent of their protein-coding activity. Mechanistically, the researchers discovered that the RNA sequences of the three genes act as ceRNAs that sponge miRNA molecules that function to inhibit tumor growth and development. Therefore, by "soaking up" the miRNA molecules and their blocking antitumor activity, the ceRNA molecules drive tumor growth and metastasis. Importantly, the researchers discovered that copy number alterations of CEP170, NUCKS1andZC3H11A were present in other tumor types, including breast, colon, liver and lung cancer, suggesting that these alterations may be important for other cancer types as well.

These results will likely change the widely held view that the key to cancer primarily relies on the structure and function of proteins and opens avenues for new investigations into a biological area that is only beginning to be studied.

"Our study challenges the notion that somatic copy number alterations promote cancer predominantly through their encoded proteins and establishes ceRNAs as potent drivers underlying the oncogenicity of somatic copy number alterations," said Florian Karreth, Ph.D., study author and assistant member of the Molecular Oncology Department.

This study was supported by the National Institutes of Health (R03CA227349, R01CA259046 and P30CA076292) and the Melanoma Research Alliance (500655).